Taylor Feehley

Commensal bacteria protect against food allergen sensitization

Significance The prevalence of food allergy is rising at an alarming rate; the US Centers for Disease Control and Prevention documented an 18% increase among children in the United States between 1997 and 2007. Twenty-first century environmental interventions are implicated by this dramatic generational increase. In this report we examine how alterations in the trillions of commensal bacteria that normally populate the gastrointestinal tract influence allergic responses to food. We identify a bacterial community that protects against sensitization and describe the mechanism by which these bacteria regulate epithelial permeability to food allergens. Our data support the development of novel adjunctive probiotic therapies to potentiate the induction of tolerance to dietary allergens. Environmentally induced alterations in the commensal microbiota have been implicated in the increasing prevalence of food allergy. We show here that sensitization to a food allergen is increased in mice that have been treated with antibiotics or are devoid of a commensal microbiota. By selectively colonizing gnotobiotic mice, we demonstrate that the allergy-protective capacity is conferred by a Clostridia-containing microbiota. Microarray analysis of intestinal epithelial cells from gnotobiotic mice revealed a previously unidentified mechanism by which Clostridia regulate innate lymphoid cell function and intestinal epithelial permeability to protect against allergen sensitization. Our findings will inform the development of novel approaches to prevent or treat food allergy based on modulating the composition of the intestinal microbiota.

The role of commensal bacteria in the regulation of sensitization to food allergens

The prevalence of life‐threatening anaphylactic responses to food is rising at an alarming rate. The emerging role of the gut microbiota in regulating food allergen sensitization may help explain this trend. The mechanisms by which commensal bacteria influence sensitization to dietary antigens are only beginning to be explored. We have found that a population of mucosa‐associated commensal anaerobes prevents food allergen sensitization by promoting an IL‐22‐dependent barrier protective immune response that limits the access of food allergens to the systemic circulation. This early response is followed by an adaptive immune response mediated in part by an expansion of Foxp3+ Tregs that fortifies the tolerogenic milieu needed to maintain non‐responsiveness to food. Bacterial metabolites, such as short‐chain fatty acids, may contribute to the process through their ability to promote Foxp3+ Treg differentiation. This work suggests that environmentally induced alterations of the gut microbiota offset the regulatory signals conferred by protective bacterial species to promote aberrant responses to food. Our research presents exciting new possibilities for preventing and treating food allergies based on interventions that modulate the composition of the gut microbiota.

Neonatal acquisition of Clostridia species protects against colonization by bacterial pathogens

Gut anaerobes protect against pathogen invasion Intestinal infections are a common problem for young animals. One explanation is that the protective gut microbiota is not fully established in infants. How the microbiota might protect against pathogens is unclear. Kim et al. found that members of the group of strictly anaerobic, spore-forming bacteria known as clostridia protect neonatal mice against diarrhea-causing pathogens. The protective effect is enhanced by giving mice the metabolite succinate in drinking water. Succinate favors colonization of the neonatal gut by cluster IV and XIVa clostridia and concomitantly excludes Salmonella typhimurium. Science, this issue p. 315 Establishment of benign anaerobic gut microbiota can be boosted by succinate to protect infant guts from pathogen invasion. The high susceptibility of neonates to infections has been assumed to be due to immaturity of the immune system, but the mechanism remains unclear. By colonizing adult germ-free mice with the cecal contents of neonatal and adult mice, we show that the neonatal microbiota is unable to prevent colonization by two bacterial pathogens that cause mortality in neonates. The lack of colonization resistance occurred when Clostridiales were absent in the neonatal microbiota. Administration of Clostridiales, but not Bacteroidales, protected neonatal mice from pathogen infection and abrogated intestinal pathology upon pathogen challenge. Depletion of Clostridiales also abolished colonization resistance in adult mice. The neonatal bacteria enhanced the ability of protective Clostridiales to colonize the gut.

Microbial regulation of allergic responses to food

The incidence of food allergy in developed countries is rising at a rate that cannot be attributed to genetic variation alone. In this review, we discuss the environmental factors that may contribute to the increasing prevalence of potentially fatal anaphylactic responses to food. Decreased exposure to enteric infections due to advances in vaccination and sanitation, along with the adoption of high-fat (Western) diets, antibiotic use, Cesarean birth, and formula feeding of infants, have all been implicated in altering the enteric microbiome away from its ancestral state. This collection of resident commensal microbes performs many important physiological functions and plays a central role in the development of the immune system. We hypothesize that alterations in the microbiome interfere with immune system maturation, resulting in impairment of IgA production, reduced abundance of regulatory T cells, and Th2-skewing of baseline immune responses which drive aberrant responses to innocuous (food) antigens.

Cellular and molecular pathways through which commensal bacteria modulate sensitization to dietary antigens.

Food allergies are a growing public health concern. The rapidly increasing prevalence of allergic disease cannot be explained by genetic variation alone, suggesting a role for gene-by-environment interactions. The bacteria that colonize barrier surfaces, often referred to as the commensal microbiota, are dramatically affected by environmental factors and have a major impact on host health and homeostasis. Increasing evidence suggests that alterations in the composition of the microbiota, caused by factors such as antibiotic use and diet, are contributing to increased sensitization to dietary antigens. This review will discuss the cellular and molecular pathways activated by commensal bacteria to protect against allergic sensitization. By understanding the interplay between the environment, the microbiota, and the host, we may uncover novel therapeutic targets that will allow us to control the allergy epidemic.

Chapter 6 – Mucosal Immunity

Mucosal surfaces form the interface of the body with the external environment and play a central role in immune surveillance and protection against infection. The surface areas that comprise the mucosa are defined by the presence of a semipermeable epithelial barrier that is reinforced by a variety of innate and adaptive immune mechanisms. Large numbers of lymphocytes that reside below the epithelium serve to protect against microbial invasion and mediate immunity to disease. Mucosal surfaces are also the home of the commensal microbiome, a diverse community of bacteria that contributes to the health of the host but must also be contained and controlled by the immune system at these sites. Overall, mucosal surfaces provide an essential barrier between the host and the outside environment and are characterized by the novel adaptations required to protect this barrier.